1. Field of the Invention
The present invention relates to a sustained-release preparation suited for sustained release of a bioactive polypeptide and a method of producing the sustained-release preparation.
2. Brief Description of the Background Art
Bioactive polypeptides or derivatives thereof are known to exhibit various pharmacological actions in vivo. As the recent advances in gene or cell engineering have enabled their production at high purity and in large amounts, an increased number of such substances have been brought into clinical application as pharmaceuticals. When orally administered, however, these bioactive polypeptides are readily decomposed by enzymes in the gastrointestinal tract, resulting in very low absorption rates. Also, many of them are short in biological half-life. For these reasons, repetitive intramuscular or subcutaneous injection or intravenous drip infusion is normally used to administer them. Although these methods are acceptable when administration frequency is limited to a few times, frequent administration in chronic diseases poses an extreme burden on the patient's body. For example, interferon a (IFN.alpha.) is given to patients with hepatitis C on consecutive days for 4 weeks or more, and growth hormone is given to infant or young patients with pituitary dwarfism by subcutaneous or intramuscular administration consecutive days or every two days for an extended period of time from several months to 10 years or more. In addition, to achieve symptom remission, complete healing or linear growth in these diseases, it is reportedly necessary to maintain clinically useful levels of active ingredients for an extended period of time. To solve this problem, there have been a large number of attempts to develop sustained-release preparations containing a bioactive polypeptide [Clinical Reviews in Therapeutic Drug Carrier Systems, No. 12, pp. 1-99 (1995)1.
WO94/19020 discloses a method of polypeptide stabilization by dissolving a mixture of polypeptide and polyol in an organic solvent. W094/12158 discloses a sustained-release preparation obtained by adding a mixture of polymer and growth hormone to an organic solvent. EPA 251476 (U.S. Pat. No. 4962091, Japanese Patent Unexamined Publication No. 2930/1988) discloses a matrix comprising a polypeptide dispersed in polylactide. Japanese Patent Unexamined Publication Nos. 46116/1992 and 65063/1994 disclose a method of producing a sustained-release preparation by dissolving a biodegradable polymer and a fatty acid salt in an organic solvent and prepared as an o/w emulsion. Japanese Patent Examined Publication No. 57658/1994 discloses a sustained-release preparation comprising a bioactive polypeptide uniformly contained in a carrier consisting of atherocollagen or the mixture of atherocollagen and gelatin. Pharmaceutical Research, Vol. 9, No. 1, pp. 37-39 (1992), Pharmaceutical Research, Vol. 11, No. 2, pp. 337-340 (1994) and the Journal of Controlled Release, Vol. 33, pp. 437-445 (1995) disclose a sustained-release preparation of bioactive polypeptide from a w/o/w/emulsion obtained by adding the polypeptide to a mixed solution of a surfactant and a polymer in an organic solvent. As stated above, most prior art methods are based on the w/o/w method wherein a surfactant, if used, and a biodegradable polymer are dissolved in an organic solvent, and an aqueous solution of a bioactive polypeptide is added to the resulting oil phase. The s/o/w method has also been reported wherein a powdered bioactive polypeptide is added directly to an oil phase containing a biodegradable polymer and, if used, a surfactant. However, all these methods fail to provide clinically practical pharmaceuticals, since decreased stability of the bioactive polypeptide significantly affects recovery rates or lowers the quality of the sustained-release preparation obtained.
Although there have been reported various attempts to produce a sustained-release preparation, while retaining the bioactivity of a bioactive polypeptide, as stated above, there have been no preparations that are clinically satisfactory in terms of the ratio of bioactive polypeptide entrapped in biocompatible polymer, suppression of initial release, long and constant sustained-release property except some preparations of LH-RH analogs and so on. Specifically, in preparations of bioactive polypeptides having higher structure, sufficient yields or pharmacological effects have not been obtained because the blood drug concentration is unexpectedly high in the initial stage after administration, because the drug release rate is not constant during the sustained-release period, or because the bioactive polypeptide is denatured during the manufacturing process. Also, in the case of sustained-release indwellable preparations, other problems arise, i.e., full compliance cannot be obtained due to pain at administration site, and the heterozoic collagen for base may be antigenic.
Thus, there is demand for the development of a clinically useful sustained-release preparation exhibiting long and constant sustained-release, while retaining the bioactivity of a bioactive polypeptide, and a method of its production.